Field of the Invention: The invention relates to the identification of human binding molecules capable of specifically binding to CD1a, to immunoconjugates comprising these binding molecules and to methods of obtaining the binding molecules. The invention further encompasses the use of the human binding molecules in medicine, in particular for the diagnosis, prevention and/or treatment of neoplastic diseases and Langerhans Cell Histiocytosis.
CD1 molecules are a family of molecules that are expressed on the surfaces of dendritic cells, monocytes, and some thymocytes. CD1 molecules are similar to MHC Class I molecules in that they are involved in antigen presentation. Five CD1 genes have thus far been identified in humans: CD1a, CD1b, CD1c, CD1d and CD1e. Four of these five CD1 gene products have been defined serologically. They are referred to as CD1a, CD1b, CD1c and CD1d and are distinguished by unique heavy chains with approximate molecular weights of 49 kDa, 45 kDa, 43 kDa and 48 kDa, respectively.
The fact that CD1a molecules are expressed by acute and chronic leukemic cells of the pre-B, B, T and non-lymphoid lineages renders CD1a in principle a target to detect or attack these disorders (Salarnone et al. (1990a), Salamone (1990b), Merle-Beral et al. (1989)).
Furthermore, CD1a molecules are present on Langerhans cells (which are the major dendritic antigen-presenting cells in the skin) (Teunissen (1992)). This renders CD1a in principle a target to detect or treat Langerhans Cell Histiocytosis (LCH), a clonal proliferative neoplasm with variable clinical manifestations, ranging from solitary, self-limiting lesions to multisystem disease that can be life threatening.
Binding molecules that specifically bind to CD1a might be very useful in diagnosis and treatment of the above-mentioned disorders. Several murine monoclonal antibodies directed against CD1a are known in the art (Kelly (1994), Amiot et al. (1986), Furue et al. (1992)). However, murine antibodies, in naked or immunoconjugated format, are limited for their use in vivo due to problems associated with administration of murine antibodies to humans, such as short serum half life, an inability to trigger certain human effector functions and elicitation of an unwanted dramatic immune response against the murine antibody in a human (the “human antimouse antibody” (HAMA) reaction) (Van Kroonenburgh and Pauwels (1988)).
In general, attempts to overcome the problems associated with use of fully murine antibodies in humans, have involved genetically engineering the antibodies to be more “human-like.” A first stage in the humanization process was preparing chimeric antibodies, i.e., antibodies in which the variable regions of the antibody chains are murine-derived and the constant regions of the antibody chains are human-derived. Subsequently, domains between the variable domains that specify the antigen binding were replaced by their human counterparts leading to so-called humanized antibodies. A disadvantage of these chimeric and humanized antibodies is that they still retain some murine sequences and therefore still elicit an unwanted immune reaction, especially when administered for prolonged periods.
In view of their benefit in therapy there is still a need for human binding molecules against CD1a.
The present invention provides human binding molecules against CD1a that can be used in medicine, in particular for diagnosis, prevention and/or treatment of CD1a-associated disorders.